The International Journal of Biochemistry & Cell Biology
ReviewPotential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases
Introduction
Within the past half-century, there has been a major breakthrough in our understanding of the cellular, molecular, genetic, and biochemical mechanisms of most chronic diseases. The discovery of growth factors, hormones, and cytokines; their receptors; protein kinases; and transcription factors have provided the basis for signal transduction at the cellular level. How these signals mediate different diseases, has also become apparent. It is now common knowledge that the products of approximately 25,000 different genes regulate the human body and that most diseases are caused by dysregulation of multiple gene products. Using microarray technology, it has been estimated that as many as 300–500 different genes may control any given chronic illness. Until now, few of these genes have been targeted for therapy. Tumor necrosis factor (TNF), cyclo-oxygenase 2 (COX-2) inhibitor, vascular epithelial growth factor (VEGF), CD20, and epidermal growth factor receptor are perhaps the best-known examples (Aggarwal et al., 2007). Another intriguing revelation is that most chronic illnesses are caused by dysregulated inflammation. For instance, inflammation has been found to play a major role in cancer, cardiovascular diseases (CVDs), pulmonary diseases, metabolic diseases, neurologic diseases, and even psychological diseases (B.B. Aggarwal et al., 2006a, Hansson et al., 2006, Garodia et al., 2007, Khanna et al., 2007, Libby, 2007, Odrowaz-Sypniewska, 2007, Robinson et al., 2007, Selmi et al., 2007, Packard and Libby, 2008, Hold and El-Omar, 2008, Dantzer et al., 2008).
Almost two decades ago, our laboratory was the first to isolate two different cytokines (TNF-α and TNF-β) as antitumor agents (Aggarwal et al., 1985a, Aggarwal et al., 1985b). It has now become clear, however, that TNF-α is a major mediator of inflammation in most diseases, and this effect is regulated by the activation of a transcription factor, nuclear factor (NF)-κB. Whereas TNF is the most potent NF-κB activator yet described, the expression of TNF-α is also regulated by NF-κB (Aggarwal, 2003). Besides TNF, NF-κB is activated by most inflammatory cytokines; Gram-negative bacteria; various disease-causing viruses; environmental pollutants; chemical, physical, mechanical, and psychological stress; high glucose; fatty acids; ultraviolet radiation; cigarette smoke; and other disease-causing factors (Aggarwal, 2004, Kumar et al., 2004, Sethi et al., 2008, Tergaonkar, 2006, Karin and Greten, 2005, Ahn and Aggarwal, 2005). Interestingly, most mediators of inflammation that have been identified up to now are also regulated by NF-κB, including inflammatory cytokines, chemokines, adhesion molecules, enzymes, and kinases (see Fig. 1). Thus, NF-κB and NF-κB-regulated gene products have been closely linked with most chronic illnesses. Therefore, agents that downregulate NF-κB- and NF-κB-regulated gene products have potential efficacy against several of these diseases.
Suppression of NF-κB activation is a topic actively being pursued in the academic and industrial settings. Our laboratory was the first to demonstrate that curcumin is a potent blocker of NF-κB activation induced by different inflammatory stimuli (Singh and Aggarwal, 1995). We and others subsequently showed that curcumin blocks NF-κB activation through inhibition of IκBα kinase and AKT (Aggarwal et al., 2005, S. Aggarwal et al., 2006, Shishodia et al., 2005, Siwak et al., 2005, Kamat et al., 2007, Deeb et al., 2007, Aoki et al., 2007), thus resulting in the suppression of NF-κB-dependent gene products that suppress apoptosis and mediate proliferation, invasion, and angiogenesis. Our laboratory more recently showed that curcumin also suppresses NF-κB activation in most tumor cells, leading to suppression of anti-apoptotic proteins and resulting in apoptosis (Aggarwal et al., 2004, Kunnumakkara et al., 2007). We also showed that curcumin could downregulate the expression of interleukin (IL)-6 protein, TNF, and various other chemokines (Jagetia and Aggarwal, 2007). Abe et al. (1999) showed that curcumin inhibited the production of IL-8, MIP-1α, MCP-1, IL-1β, and TNF-α induced by inflammatory stimuli in human peripheral blood monocytes and alveolar macrophages. We and others subsequently showed that curcumin downregulates the expression of the NF-κB-regulated gene products such as COX-2, TNF, 5-LOX, IL-1, IL-6, IL-8, MIP-1α, adhesion molecules, c-reactive protein (CRP), CXCR-4, and others (Skommer et al., 2007, Shakibaei et al., 2005, Shishodia et al., 2005, Li et al., 2004) (see Fig. 1). Curcumin has also been reported to bind to COX-2 and 5-LOX and to inhibit their activity (Hong et al., 2004). Recent work from our laboratory has shown that curcumin directly binds to IkBα kinase needed for NF-κB activation (S. Aggarwal et al., 2006). Our laboratory was the first to demonstrate that curcumin is a potent inhibitor of STAT 3, another transcription factor through which proinflammatory cytokine IL-6 mediates its effects (Bharti et al., 2003a). Thus curcumin could suppress inflammation through multiple pathways.
The effect of curcumin against various proinflammatory diseases is discussed in detail in this report.
Section snippets
Role of curcumin in the treatment of chronic inflammatory diseases
In various chronic illnesses in which inflammation is known to play a major role, curcumin has been shown to exhibit therapeutic potential. These diseases include Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, epilepsy, cerebral injury, CVDs, cancer, allergy, asthma, bronchitis, colitis, rheumatoid arthritis, renal ischemia, psoriasis, diabetes, obesity, depression, fatigue, and AIDS (see Table 1). How curcumin mediates its activity against these diseases is described in
Bioavailability of curcumin
That curcumin exhibits poor bioavailability is well documented (Anand et al., 2007, R.A. Sharma et al., 2007). The major reasons attributed to the low bioavailability of curcumin are poor absorption, rapid metabolism, and rapid systemic elimination. In humans a comprehensive pharmacokinetic data do not exist. The pilot studies summarized that low systemic bioavailability is observed in humans following oral dosing. First phase I clinical trial of curcumin was done in 25 patients with high-risk
Potential side effects of curcumin
Food and drug administration has declared curcumin as “generally regarded as safe” GRAS. Even though curcumin exhibits a wide variety of pharmacological activities and has been found to be quite safe in animals and humans, there are some reports concerning its toxicity (Lopez-Lazaro, 2008). The National Toxicology Program (NTP) evaluated the short term as well as long-term toxicity of turmeric oleoresin (79–85% curcumin) in F344/N rats and B6C3F1 mice. Animals were fed diets containing the
Conclusions
The wisdom and scientific credentials of curcumin in the Ayurvedic and Chinese systems of medicine have been corroborated by numerous studies conducted over the past 30 years. These observations are also supported by epidemiological data suggesting lower incidence of chronic diseases in people from countries where curcumin is consumed. The various effects of curcumin have been widely studied in Western systems of medicine for decades, and has been found to possess antioxidant and
Acknowledgement
We would like to thank Vickie J. Williams for carefully proofreading the manuscript and providing valuable comments. We would like to thank Preetha Anand and Vijayalekshmi Nair for assistance with references. Dr. Aggarwal is a Ransom Horne, Jr., Professor of Cancer Research. This work was supported by a grant from the Clayton Foundation for Research to B. B. A., and the National Institutes of Health core grant (CA16672).
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